The overall objective of the proposal is to develop an understanding of the in vivo behavior of antineoplastic noble metal complexes, particularly cis-dichlorodiammineplatinum (II) (CDDP), so as to enhance their clinical effectiveness. This objective will be met by developing a physiological-anatomical based pharmacokinetic model for CDDP disposition in animals and man. To develop such a model it will be necessary to 1) elucidate major biodegradation products (formed both enzymatically and chemically) of CDDP and 2) develop sensitive and specific analytical methodology to monitor CDDP and its major biodegradation products occurring in biological fluids and tissues. It is necessary not only to isolate and identify the breakdown products but also to characterize their chemical reactivities. Initially, biotransformation of CDDP is to be studied in vitro in human blood and plasma, since we have already determined that extensive transformation occurs in these fluids. Although some of the products of CDDP reaction in plasma or other fluids may be too short-lived to permit them to be monitored, as major (relatively stable) "metabolites" are isolated and identified, the analytical methodology for the CDDP system will be expanded to allow the time course of these products to be followed. As the chemistry of CDDP in biological fluids becomes better understood and methodology is available to specifically monitor platinum species derived from the parent, a more realistic pharmacokinetic description of CDDP disposition can be generated. In this way it may be possible to understand and isolate the factors associated with the efficacy and toxicity observed with this agent and ultimately enhance the clinical effectiveness of CDDP and other anti-neoplastic noble metal coordination complexes.